Overall Hepatitis C Virus (HCV) chronically infects ~185 million people worldwide and is a major cause of liver failure and hepatocellular carcinoma. With the advent of oral, interferon-sparing HCV regimens, it has become much easier to safely and effectively treat HCV infection. However, HCV control is not likely to be achieved with treatment alone. Identification of those with HCV infection is challenging, therapies are too costly for countries with the highest incidence, reinfection can occur following treatment, transmission of drug-resistant HCV is possible, and treatment does not fully reverse severe liver damage even when cure is achieved. There is a rising epidemic of acute HCV infection in adolescents and young adults in the United States that gives new urgency to prophylactic vaccine development efforts. However, numerous challenges for vaccine development remain, including limited populations in which candidate vaccines can be tested, the enormous sequence diversity of HCV, and incomplete understanding of what mediates protective immunity. The study of immune responses to HCV has provided important insight into protective immunity. However, more research is needed to identify clear correlates of immunity to assess in healthy volunteers before candidate vaccines are tested in the limited at-risk populations available. The overall goal of this proposed research is to define the innate, humoral, and T cell responses that allow protective immunity against the broadest array of infecting hepatitis C viruses by studying people who are repeatedly exposed to and control HCV. This research will include an assessment of the earliest innate response to infection as well as the downstream adaptive response to help select a vaccine adjuvant that enhances induction of protective responses. The sequence of HCV will be compared before and after induction of adaptive immune responses to better understand how the virus, with its remarkable sequence diversity, is able to evade immune responses. The knowledge gained about humoral responses to HCV will be used to design vaccines to elicit antibodies that neutralize HCV infection. Understanding protective T cell responses will enhance creation of a vaccine that induces T cells capable of clearing cells infected with any virus that evades the frontline neutralizing antibodies. In sum, we anticipate that the proposed research studying people who are repeatedly exposed but don't develop persistent HCV infection will define correlates of protective immunity to target in vaccine design.